The seriousness and prevalence of heart disease is well known to people in the medical arts. Heart attacks represent a major cause of death, particularly in industrial countries such as the U.S. During the first months following a heart attack the overall mortality rate is about 30%, with most deaths occurring in the first 24 to 48 hours. Heart attacks, or myocardial infarction (MI) may be described as ischemic necrosis that is due to partially or completely blocked coronary arteries in the heart which starves the heart muscle for nutrients and oxygen. When the deprivation of oxygen and nutrients is severe, the tissue dies and is replaced by scar tissue which is not useful as heart muscle. The patient's heart muscle is usually weakened permanently, to some degree by such scar tissue.
The substantial narrowing or occlusion of a coronary artery may be caused by thrombus (clot), by atherosclerosis, by hemorrhage into an atherosclerotic plaque, or by spastic constriction of a coronary artery. Any one of the above mechanisms or a combination of them may cause a MI.
Treatment for patients who have suffered a myocardial infarction has largely been one of containment and stabilization. Symptomatic treatment is given. The damaged vascular or myocardial system is not rebuilt. See, for example, Krupp et al, Current Medical Diagnosis and Treatment, Lang Medical Publications, Los Angeles, Calif. (1985). Recently, "thrombolytic" therapy has advanced the treatment of MI. In the first hours after infarction, streptokinase or tissue plasminogen activator (tPa) can dissolve blood clots in coronary arteries, restoring blood flow to the heart muscle and avoiding infarction. Again, the underlying damaged myocardial vasculature is not altered by this mode of treatment.
After a MI, treatment usually consists of rest; sedation; pain killers (analgesics); oxygen; drugs to reduce the work of the heart; anticoagulants to avoid possible further clots and damage; vasodilators and diuretics to lower blood pressure; coronary vasodilators such as nitroglycerin to relax the coronary arteries and cause the blood flow to improve, inotropic agents such as digitalis to slow the heart beat; and aortic balloon counter pulsation as a circulatory assistant. Current treatment will sometimes include reopening a severe blockage by balloon catheters or similar devices (angioplasty), or use of bypass surgery. Drugs are sometimes given to prevent platelet aggregation and avoid recurrent MIs for several months following the heart attack. For this purpose .beta.-adrenergic blocking drugs are also sometimes administered.
In order to rehabilitate patients, gradual return to work and increases in exercise are generally prescribed.
In addition to the above treatments for a MI, current practice also includes preventative measures. To remedy these blocked arteries and to avoid deprivation causing scar tissue to the heart, physicians have used mechanical methods to improve the cardiac blood flow. One method involves improving cardiac blood flow by surgically bypassing diseased vessels (coronary artery bypass surgery). This involves open heart surgery where a blood vessel is taken from some other part of the body and attached to the blocked artery both in front of the blockage and beyond of it in order to bypass the obstruction and cause the blood flow to go around the blockage.
Another method for mechanically improving cardiac blood flow by opening the existing diseased vessels is called percutaneous transluminal coronary angioplasty (PTCA). This method involves inflation of a balloon inside the blood vessel at the blockage point to crack and compress the atherosclerotic material outward, hence enlarging the diameter of the vessel. In this balloon surgery, a stent a stint (a device to keep the walls of the artery from collapsing back upon themselves) may be inserted at the blockage point.
There are serious drawbacks for each of the above procedures, and none are always satisfactory. A vein is usually used for the bypass. Since a vein is flatter and has thinner walls than an artery, the vein used for the bypass also tends to become blocked. The other two methods cause damage to the artery, and the healing response of the artery to this injury often causes the buildup of a type of scar tissue which itself causes significant obstruction of the vessel. This phenomenon is called "restenosis", and it occurs in 35 to 45% of cases.
Another temporary measure for treating the heart soon after a myocardial infarction is described in U.S. Pat. No. 4,296,100, issued to Franco on Oct. 20, 1981. A fibroblast growth factor (FGF), obtained from bovine pituitary glands is used to treat the heart in vivo after myocardial infarction in amounts of 10 mg to 1 gram per 100 grams of heart of the about 90% pure FGF. A series of spaced injections (different locations in the heart) are used to distribute the desired amount of FGF over the area of the heart to be treated. This direct injection into the heart or intravenous injection is preferred. However, subcutaneous, intramuscular and oral injection is also described.
These injections described by Franco collectively concern a one-time treatment immediately following a myocardial infarction (injections are given during one 24 hour period of time) This treatment is given as close to the time the heart attack as possible in order to control damage, i.e., to immediately improve circulation and thus avoid further damage to the heart. Franco neither describes nor suggests continued or multiple treatments with FGF to improve a damaged heart or to continue to improve circulation. See column 3 and column 4. The experiments of Franco showed that by using a one time treatment he was able to reduce the infarct size (area that will scar or remain premanently damaged) in the test animal to one quarter the size of the control (non-treated) hearts. Histological study did not show any significant increase in capillary areas in the hearts as a result of such treatment with FGF. The study merely showed that the damage to animal hearts was significantly less than damage to those hearts treated with the control and no FGF. See page 4, lines 11-17, for example.
The above data related to the Franco patent could not have related to the growth of blood vessels to treat a heart attack for additional reasons. This is because blood flow must be restored to the jeopardized muscle within 6 to 8 hours to save it, and blood vessels can not possibly grow that fast. Further, some reliable data has been published recently in a peer-reviewed journal which indicates that application of fibroblast growth factor in the context of infarction may actually be dentrimental to the patient. (See, for example, Banai et al.: Effects of acidic fibroblast growth factor on normal and ischemic myuocardium, Circulation Research 69, pages 76-85 (1991)).
U.S. Pat. No. 4,778,787, issued Oct. 18, 1988 to Catsimpoolas et al, relates to treating the heart with angiogenesis healing factors. Catsimpoolas does not relate to treatment with a peptide or protein growth factor. Instead, this patent relates to treatment with omentum-derived lipid fractions, for example, from cat omentum.
Catsimpoolas et al. describe systemic (and/or local) application of omentum-derived lipid fractions or the use of their bio- or organic-synthetic or purified analogs for the acceleration of vascularization, neovascularization, vascular collateralization, promotion of perfusion, and collagen formation or scarring and organization (cellular and collagenous) of myocardiac ischemic lesions. This was regarded as surprising since lipid materials are often considered to be atherosclerotic agents which cause MIs rather than preventing them. This patent relates to the accelerated repair of a heart after MI with less scarring than would be ordinarily expected.
There is no technology in existence at the present time that can foster the in vivo growth of new blood vessels in the heart, thereby improving cardiac blood flow. That is why the somewhat unsatisfactory procedures described above are still necessary to improve cardiac blood flow.
During the last six years, a number of proteins have been characterized that promote the growth of blood vessels in vitro. Despite their great promise in the treatment of cardiovascular disease, none have been successfully utilized in vivo to date. Moreover, to the present date, there has been no publication of any data directed to using any of these proteins in vivo to generate any blood vessels in mature tissue, i.e., in non-embryonic tissue.
As stated above, polypeptides, to date, have not been successively used to promote the growth of blood vessels in the heart, to regenerate vessels in a damaged or nearby area in a heart, or over a period of time to increase cardiac blood flow in a damaged area. The focus of the prior art has been upon the prevention of damage immediately following arterial blockage in the heart or brain. Moreover, there is no method in the prior art to provide these results or any directional details or discussion relating to a suitable dosage for accomplishing regeneration of new cardiac blood vessels.
Accordingly, there is an acute need in this art for a means to target agents directly to the heart in order to actually cause or promote the growth of new cardiac blood vessels in a limited desired area and improve critical blood flow to the heart. There is a pressing need in the art for the above method to treat the millions of patients suffering with atherosclerosis of the coronary arteries. Such an approach is needed that can potentially partially or completely replace blocked coronary arteries with new blood vessels without affecting the degree of vascularity in the area of the body.